The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
Tumor necrosis factor (TNF) alpha is a potent pro-inflammatory cytokine which plays a central role in immune responses and inflammatory disorders. It has been described as key mediator of inflammatory, immunological and pathophysiological reactions. Primarily secreted by monocytes and activated macrophages, TNF alpha is also produced by numerous other cell types, including fibroblasts, neutrophils, eosinophils and epithelial cells.
Also termed cachectin, TNF alpha exists in two biologically active forms: a transmembrane and a soluble form. The soluble form of TNF alpha is released from the transmembrane TNF alpha (tmTNF alpha) by proteolytic cleavage. Both TNF alpha forms are biologically active trimers, bind TNF receptors and exert various biological functions to contribute to the host defence. In addition, both the transmembrane and the soluble TNF alpha play a role in the pathogenesis of inflammatory and autoimmune diseases.
Two receptors for TNF alpha were identified (TNF-R1 and -R2) mediating the pleiotropic TNF alpha effects. Said receptors are expressed on a variety of cells, mainly on monocytes and macrophages. Receptor activation triggers the various biological effects, including pro-inflammatory cytokine production such as IL-1, TNF alpha, IL-6, IL-8; chemokine production; neutrophil activation; increases endothelium layer's permeability; and expression of adhesion molecules. Accordingly, a large number of diseases is associated with up-regulated TNF alpha levels and consequently, TNF alpha inhibitors have found ample use in medical treatment. An important subclass of the ever growing number of TNF alpha inhibitors are biological drugs. A number of biological inhibitors of TNF alpha received regulatory approval and are commercially available. One group of such biological inhibitors are full-length immunoglobulins. For example, infliximab (Remicade®), a chimeric IgG of about 150 kDa, has been approved in the treatment of Crohn's disease, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, psoriasis, and Behçet disease. Adalimumab (Humira®), an IgG1 of about 150 kDa, is approved for rheumatoid arthritis, juvenile rheumatoid arthritis, Crohn's disease, psoriatic arthritis, psoriasis, ankylosing spondylitis, ulcerative colitis and Behçet disease. Finally, golimumab (Simponi®), a human IgG1 of about 150 kDa molecular weight, is approved in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis.
Still, some approved biological TNF alpha inhibitors deviate from the full-length immunoglobulin structure. For example, etanercept (Enbrel®) is a TNF-receptor 2 extracellular domain Fc fusion protein with a molecular weight of 150 kDa which has been approved for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, psoriasis and ankylosing spondylitis. Further, certolizumab pegol (Cimzia®), a humanized Fab-PEG conjugate of about 90 kDa, is approved and widely used in the treatment of Crohn's disease and rheumatoid arthritis.
Despite the advances in the field, there remains a need for biologics with an optimal combination of biophysical features. For example, topical treatment of skin diseases, i.e. applying TNF alpha inhibitors topically to the skin, would be a much preferred application route as the side-effects of systemic treatment could be avoided. However, to date, such treatment is not feasible, inter alia, as the currently approved immunotherapeutics are too large and hence cannot cross the skin stratum corneum and/or due to the drug production costs.
The key role of TNF alpha in psoriasis and psoriatic arthritis is well established (see, e.g., CORDORO, K M and FLEDMAN S R. TNF-alpha inhibitors in dermatology. Skin Therapy Letter 2007, vol. 12, pp. 4-6). Psoriasis is a frequent disease with a prevalence of 2-3%. While milder forms can be treated topically with glucocorticoids and/or vitamin D3-analogues, more severe forms require systemic treatment including cyclosporine, methotrexate or eventually biologics (Prieto-Pérez R. et al, Pharmacogenomics. 2013 October; 14(13):1623-1634). The introduction of biological therapies for the systemic treatment of severe psoriasis involving the use of monoclonal antibodies targeting e.g. TNF alpha (adalimumab, etanercept and infliximab) has substantially addressed the medical need of patients suffering from severe forms of psoriasis. While highly effective, these drugs are associated with a number of potentially severe and serious adverse events. Therefore, the benefit/risk profile of these drugs precludes the majority of psoriasis patients presenting with mild to moderate forms of psoriasis. Side effects could e.g. be reduced through local application of biological drugs, i.e. topical administration. However, due to their large size, full-length antibodies are not suitable for such a route of administration.
Hidradenitis suppurativa, also termed acne inversa, is another TNF alpha related disorder. Said inflammatory chronic disease is characterized by clusters of abscesses in the apocrine gland bearing skin, such as the axilla, inner thighs, groin and buttocks (SCHEINFELD, N. Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients. Dermatol Online Journal 2013, vol 19, p.1.) TNF alpha inhibitors have successfully been used in the treatment of said orphan disease (Brunasso A M, Massone C. Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors: An update on infliximab. Acta Derm Venereol. 2011, vol. 91(1), pp.70; Sotiriou E. et al, Etanercept for the treatment of hidradenitis suppurativa, Acta Derm Venereol. 2009, vol. 89(1), pp. 82-3). Antibodies directed against TNF alpha have also been efficient in the treatment of pyoderma gangrenosum, another orphan skin disease (Reddick C L et al. Successful treatment of superficial pyoderma gangrenosum associated with hidradenitis suppurativa with adalimumab. Dermatol Online J. 2010, vol. 16(8), pp.15). To date, no biological drug has been approved for the treatment of such orphan diseases, however, commercially available biologics are used off-label.